EP2944326B1 - Conjugués de tricarbocyanine-cyclodextrine et leur utilisation pour le diagnostic de maladies du rein - Google Patents
Conjugués de tricarbocyanine-cyclodextrine et leur utilisation pour le diagnostic de maladies du rein Download PDFInfo
- Publication number
- EP2944326B1 EP2944326B1 EP15167540.2A EP15167540A EP2944326B1 EP 2944326 B1 EP2944326 B1 EP 2944326B1 EP 15167540 A EP15167540 A EP 15167540A EP 2944326 B1 EP2944326 B1 EP 2944326B1
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- European Patent Office
- Prior art keywords
- formula
- cyclodextrin
- hydroxypropyl
- tricarbocyanine
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- Prior art date
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/16—Cyclodextrin; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B69/00—Dyes not provided for by a single group of this subclass
- C09B69/10—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds
- C09B69/105—Polymeric dyes; Reaction products of dyes with monomers or with macromolecular compounds containing a methine or polymethine dye
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
Definitions
- the present invention relates to novel tricarbocyanine-cyclodextrin(s) conjugates, and use thereof as diagnostic agents for kidney diseases.
- Fructans are used as markers in kidney diagnostics and in particular to determine the glomerular filtration rate (GFR) as a test for kidney function.
- GFR glomerular filtration rate
- Fructans are straight or branched chain oligosaccharides and polysaccharides with an sucrose terminal end. Fructans can have different physical properties, such as water solubility depending on the degree of branching and polymerization. Fructans occur in plants as carbohydrate reserves. As a natural product the fructans have an unpredictable length.
- the fructans inulin and sinistrin are used in particular as markers in kidney function tests.
- Inulin and sinistrin are composed of 10 to 40 fructose units with a corresponding molecular weight of 1600 to 6500 Da. After intravenous injection, inulin and sinistrin are neither changed nor stored in the organism, but they are filtered out by the kidney glomeruli and are not reabsorbed again in the tubuli. The filtration of the fructans may vary according to their size.
- the concentration marker in the blood may, for example, be determined by enzymatic methods, as described in Kuehnle et al., Nephron, 62, 104-107 (1992 ). This method is time consuming, very cumbersome and of limited use.
- inulin and FITC-inulin for the clinical routine analyses are their very low solubility in water.
- the preparations containing insulin and FITC-insulin have to be heated to 90°C until complete dissolution ( Rieg, T. A High-throughput Method for Measurement of Glomerular Filtration Rate in Conscious Mice. J. Vis. Exp. (75), e50330, doi:10.3791/50330 (2013 )), as their aqueous solutions tend to crystallize during storage.
- this causes a partial degradation of inulin to fructose.
- the solution has to be then dialysed for 24 hr at room temperature.
- This step is especially important to FITC-inulin in order to remove unconjugated FITC, but also the byproducts generated by the heating procedure. Dialysis substantially decreases the concentration of FITC-inulin. In addition, the low solubility of inulin and FITC-inulin makes it difficult to achieve a well defined concentration and to handle the marker during the injection.
- Cy5.5-inulin conjugate has been introduced by Perkin-Elmer (GFR-Vivo; application note by Peterson, J. D, Perkin-Elmer Corporation).
- An advantage of Cy5.5-inulin conjugate over FITC-inulin is related to the excitation/emission wavelengths of Cy5.5 (675/705 nm).
- the longer wavelength of Cy5.5 allows a deeper tissue penetration, but its use with a small animal imager requires the animals being anesthetized.
- Anesthesia however, has an unpredictable impact on blood pressure (initial rise, decrease during the major phase of anesthesia, followed by a rise at the ending phase). Kidney perfusion and thus GFR are highly sensitive to blood pressure, with low blood pressure values resulting in low GFR values. Thus, a meaningful/reproducible GFR measurement is not possible under anesthesia.
- inulin and also sinistrin are natural products; their composition is quite variable even within the same batch, and even more in different batches. For Regulatory Affairs this is not acceptable.
- WO2012/097223 discloses fluorescent compounds comprising a tricarbocyanine residue connected to a linear hexasaccharide through a triazol linker.
- the object of the present invention is to provide a novel substance which can be used as marker in a kidney function test which overcome the disadvantages of the markers known in the prior art.
- the invention relates to fluorescent tricarbocyanine-cyclodextrin(s) conjugates as markers for kidney function tests in mammals.
- An embodiment of the present invention relates to a fluorescent compound of formula (I) F-L n -CD n (I) wherein F is a tricarbocyanine residue of formula (II) wherein
- a further embodiment of the present invention relates to a diagnostic formulation comprising at least one fluorescent compound of formula (I) for use in diagnostic tests for determining the kidney function parameters, preferably the glomerular filtration rate (GFR), of a mammal.
- GFR glomerular filtration rate
- a further embodiment of the present invention relates to a method for screening pharmaceutical compounds suitable for treatment of chronic kidney diseases, wherein the method comprises:
- the invention relates to fluorescent tricarbocyanine-cyclodextrin(s) conjugates as markers for kidney function tests.
- fluorescent conjugates that are the object of the present invention, are represented by the general formula (I) F-L n -CD n (I) wherein F is a tricarbocyanine residue of formula (II) wherein
- Dyes belonging to the class of cyanines have already found some use in clinical diagnostics; in particular, Indocyanine Green has been used for kidney function test and fluorescence angiography for more than 30 years.
- Tricarbocyanine dyes absorb and emit light in the near-infrared region (NIR) (650-900 nm). Tricarbocyanine dyes are especially suitable for in vivo imaging, diagnostics and even therapeutics, since biological tissues are relatively poor absorbers in the near-infrared spectral region, and infrared light can penetrate deeply in such tissues; in addition, these dyes do not give origin (or at very low amount) to auto-fluorescence in the near-infrared spectral region.
- NIR near-infrared region
- Cyclodextrins are cyclic oligosaccharides produced by the enzymatic degradation of starch. Depending on reaction conditions, three main CDs can be obtained a, ⁇ and ⁇ ; they consist of 6, 7 or 8 glucopyranose units. They are shaped as a truncated cone, with hydroxyl groups on each side. Their cavity is constituted by the glucosidal moieties. These three dimensional structures result in a high external hydrophilicity and internal hydrophobicity.
- CDs are selected from ⁇ - and ⁇ -cyclodextrins, that is, CD in which m parameter of formula (III) has a value about of 7 ( ⁇ -cyclodextrin) or 8 ( ⁇ -cyclodextrin), respectively.
- At least one of the groups R', R", R'" of formula (III) is selected from OCH 3 , OCH 2 CH 3 , OCH 2 CHOHCH 3 , provided that at least one group R', R", R'" is OH.
- R' and R" are OH
- R'" is selected from OCH 3 , OCH 2 CH 3 , OCH 2 CHOHCH 3 , preferably is OCH 2 CHOHCH 3 , in which the substitution degree of R'" is between 0.5 and 1.5 per unit of formula (III).
- cyclodextrins of formula (III) are selected from 2-hydroxypropyl cyclodextrins (HCD), and in particular 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD, whose chemical structure is shown in Figure 2, and 2- hydroxypropyl- ⁇ -cyclodextrin (HyCD).
- H ⁇ CD and H ⁇ CD have been found to be non-toxic in mice and rabbits [ Pitha, J. "Amorphous water soluble derivatives of cyclodextrins: non toxic dissolution enhancing excipients.” J. Pharm. Sci. 1985, 74, 987 ]. H ⁇ CD and H ⁇ CD are widely used to improve the water solubility of drugs.
- H ⁇ CD and H ⁇ CD represent advantageous substitutes of fructans, such as inulin and sinistrin, as components of fluorescent markers for the determination of GFR, as they are relatively inexpensive, non-toxic, structurally well-defined, synthetic products, with a strong solubilizing power.
- the conjugate of formula (I) presents from 1 to 4 linker groups L to allow conjugation of 1 to 4 cyclodextrin molecules to one tricarbocyanine molecule.
- R 1 and R 2 groups are independently selected from H, SO 3 H, CO 2 H.
- R 3 and R 4 groups are independently selected from methyl, ethyl, (CH 2 ) 5 COOH, (CH 2 ) 4 SO 3 H, (CH 2 ) 3 N + (CH 3 ) 3 .
- R 5 group is selected from H, Cl, or
- the linker group L is selected from an ester, an ether, an amide, a thiocarbamate, a thiourea, a thioether, a 1,2,3-triazole, or
- CD is 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD)
- the linker L of Formula (I) (corresponding to the value of the n parameter of formula (I) equal to 1) is an ester bond formed in the coupling reaction of the carboxyl group of the tricarbocyanine (corresponding to
- CD is 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD)
- the linker L of Formula (I) (corresponding to the value of the n parameter of formula (I) equal to 1) is an ester bond formed in the coupling reaction of the carboxyl group of the tricarbocyanine (corresponding to
- CD is 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD)
- the linker L of Formula (I) (corresponding to the value of the n parameter of formula (I) equal to 1) is an ester bond formed in the coupling reaction of the carboxyl group of the tricarbocyanine (corresponding
- CD 1 and CD 2 are, independently, 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD)
- the linkers L of Formula (I) (corresponding to the value of the n parameter of formula
- CD 1 and CD 2 are, independently, 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD)
- the linkers L of Formula (I) (corresponding to the value of the n parameter of formula
- CD 1 , CD 2 and CD 3 are, independently, 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (
- CD 1 , CD 2 and CD 3 are, independently, 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD
- CD 1 , CD 2 , CD 3 and CD 4 are, independently, 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD)
- CD is a 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD) or 2-hydroxypropyl- ⁇ -cyclodextrin (H ⁇ CD)
- the linker L of Formula (I) (corresponding to the value of the n parameter of formula (I) equal to 1) is an ester bond formed in the respective coupling reaction of a carboxyl group
- the present invention relates to the use of at least one fluorescent compound of formula (I) or a diagnostic formulation comprising at least one fluorescent compound of formula (I) in kidney diagnostics, preferably in measuring the glomerular filtration rate (GFR), in a mammal.
- GFR glomerular filtration rate
- the mammal is a mouse, a rat, a guinea pig, a cat, a dog, a sheep, a goat, a pig, a cow, a horse, a primate.
- the present disclosure describes a method of diagnosing the glomerular filtration rate of a mammal, preferably the glomerular filtration rate (GFR), wherein at least one compound of formula (I) or a diagnostic formulation comprising at last a compound of formula (I) is administered to a mammal and the fluorescent signal emitted from the dye of compound of formula (I) is detected and measured.
- GFR glomerular filtration rate
- the at least one compound of formula (I) or the diagnostic formulation comprising at least one compound of formula (I) is administered to the mammal via a parenteral route.
- the diagnostic method herein disclosed is non-invasive, because the detection and measurement of the fluorescence emitted from the at least one compound of formula (I) are realized by detecting and measuring the fluorescent emission emerging from the skin of the mammal in response to excitation with a red light or near infrared light source, preferably by means of a sensor device placed onto the mammal skin.
- the method is accomplished in a clinically relevant period of time. That is, that period of time is such to allow the absorption of the compound of formula (I) in the blood of the mammal and the following secretion by the kidney system.
- a compound of formula (I) can be used for screening pharmaceutical compounds (test agents) suitable for treatment of chronic kidney diseases.
- the screening method comprises:
- Mammalian models of chronic kidney diseases in, for example, mice, rats, guinea pigs, cats, dogs, sheep, goats, pigs, cows, horses, and primates may be created by causing an appropriate direct or indirect injury to the kidney tissue of the animal.
- Animal models of acute kidney failure may, for example, be created by inducing in the animal the conditions or diseases such as acute interstitial nephritis or acute tubular necrosis, for example by the controlled administration of nephrotoxic agents (e.g., antibiotics, aminoglycoside drugs, heavy metals).
- nephrotoxic agents e.g., antibiotics, aminoglycoside drugs, heavy metals.
- a fluorescent tricarbocyanine dye ABZWCY (4) was synthesized and linked to H ⁇ CD, according to Example 1 and Reaction Schemes 1-4.
- the resulting ABZWCY-H ⁇ CD conjugate exhibited excellent water solubility with concentrations reaching more than 100 mg/mL.
- PPB plasma protein binding
- the noninvasive real-time monitoring of plasma clearance resulted in a half-life of approximately 17 ⁇ 2 min.
- the tricarbocyanine-cyclodextrin marker did not exhibit significant differences in plasma clearance half time in the absence and presence of a compound able to inhibit tubular secretion. This means that kidney tubular secretion is not a significant elimination pathway for these markers in a mammal.
- the present marker was exclusively cleared by the kidneys, with no appreciable nonspecific background signal in all the tissues and organs and only fluorescence signal remaining in the bladder 2 h post injection. In conclusion, such a fluorescent compound is highly suitable as exogenous fluorescent tracer for monitoring GFR.
- H ⁇ CD 2-hydroxypropyl- ⁇ -cyclodextrin
- ABZWCY-H ⁇ CD/plasma stock solution was prepared by incubation of 500 ⁇ g/ml ABZWCY-H ⁇ CD (in PBS solution) with rat plasma protein at 37°C for 1 hour.
- Plasma clearance half-life was analysed in combination with an electronic near infrared device for the transcutaneous fluorescence detection in rat models.
- This device for transcutaneous fluorescence detection.
- This device (sensor plaster), described in detail in US2011230739A1 , "Transcutaneous Organ Function Measurement”, consists of (a) a plaster which can be stuck onto the skin surface; (b) a near infrared emitting diode; (c) a radiation detector.
- the adhesive surface of the sensor plaster laterally encloses the detector to prevent ambient light from being able to pass to the detector.
- the near infrared radiation peak at about 680 nm
- the sensor plaster is electrically connected to an electronic device comprising a microcontroller and a battery, for data acquisition and their RFID transmission to an external computer ( Figures 5 and 6 ).
- An ABZWCY-H ⁇ CD/plasma stock solution is prepared by incubation of 500 ⁇ g/ml ABZWCY-H ⁇ CD (in PBS solution) with rat plasma protein at 37°C for 1 hour.
- Plasma clearance kinetics for ABZWCY-H ⁇ CD is shown in Figure 6 : (a) 1 exponential fitting (1e); (b) 3 exponential fitting (3e).
- Electronic near infrared device for transcutaneous fluorescence detection As described above.
- Plasma clearance kinetics for ABZWCY-H ⁇ CD in the presence of Probenecid is shown in Figure 7 : (a) 1 exponential fitting (1e); (b) 3 exponential fitting (3e).
- Plasma clearance half-life values measured in Examples 3 and 4 are summarized in Table 2.
Claims (12)
- Composé fluorescent de formule (I)
F-Ln-CDn (I)
où
F représente un résidu de tricarbocyanine de formule (II)R1 et R2 sont choisis indépendamment parmi H, SO3H, CO2H, SO2NH2, CH2COOH, NH2, NHCOCH2I, NO2, Br, Cl, CH3;R3 et R4 sont indépendamment choisis parmi un alkyle en C1 à C4, (CH2)3C≡CH, (CH2)4C≡CH, (CH2)5COOH, (CH2)3SO3H, (CH2)4SO3H, (CH2)3NH2, (CH2)4NH2, (CH2)3N+(CH3)3, (CH2)5N+(CH3)3, (CH2)3N3, (CH2)4N3, (CH2)3NHCOCH2I, (CH2)4NHCOCH2I, (CH2CH2O)2CH3, (CH2CH2O)3CH3, (CH2CH2O)4CH3,X est choisi parmi NH, O, S ;j est un entier allant de 1 à 4 ;k est un entier allant de 1 à 4 ;CD représente un résidu de cyclodextrine de formule (III)m est un entier égal à 6, 7 ou 8,R', R", R'" sont choisis indépendamment parmi OH, OCH3, OCH2CH3, OCH2CHOHCH3, OCHOHCH3, OCH2COOH, O(CH2)4SO3H, N3, NH2, NHCOCH3, OCH2C≡CH, SH ;L représente un groupe de liaison résultant du couplage de la tricarbocyanine de formule (II) avec la/les cyclodextrine(s) de formule (III) selon le tableau suivant :Groupe fonctionnel de la tricarbocyanine (F) dans l'un des groupes R3, R4 et R5 Groupe fonctionnel de la cyclodextrine (CD) dans l'un des groupes R', R" et R'" Groupe de liaison (L) COOH OH -C(O)O- COOH NH2 -C(O)NH- NCS OH -NC(S)O- NCS NH2 -NC(S)NH- NH2 COOH -NHC(O)- NHCOCH2I SH NHC(O)CH2S- C≡CH N3 N3 C≡CH dichlorotriazine OH dichlorotriazine OH, OH dichlorotriazine OH, NH2 n est un entier allant de 1 à 4 etdes sels de celui-ci. - Composé fluorescent selon la revendication 1, dans lequel m est égal à 7 ou 8.
- Composé fluorescent selon la revendication 1 ou 2, dans lequel au moins l'un des groupes R', R", R'" est choisi parmi OCH3, OCH2CH3, OCH2CHOHCH3, à condition qu'au moins un groupe parmi R', R", R'" représente OH.
- Composé fluorescent selon l'une quelconque des revendications précédentes, dans lequel R' et R" représentent OH, et R'" est choisi parmi OCH3, OCH2CH3, OCH2CHOHCH3, de préférence R'" représente OCH2CHOHCH3, où le degré de substitution de R'" est compris entre 0,5 et 1,5 pour chaque unité de formule (III).
- Composé fluorescent selon l'une quelconque des revendications précédentes, dans lequel R1 et R2 sont indépendamment choisis parmi H, SO3H et COOH.
- Composé fluorescent selon l'une quelconque des revendications précédentes, dans lequel R3 et R4 sont indépendamment choisis parmi un méthyle, un éthyle, (CH2)5COOH, (CH2)4SO3H, (CH2)3N+(CH3)3.
- Composé fluorescent selon l'une quelconque des revendications précédentes, choisi parmi :un composé de formule (IV) :un composé de formule (V) :un composé de formule (VI) :un composé de formule (VII) :un composé de formule (VIII) :un composé de formule (IX) :un composé de formule (X) :un composé de formule (XI) :un composé de formule (XII) :un composé de formule (XIII) :un composé de formule (XIV) :un composé de formule (XV) :un composé de formule (XVI) :un composé de formule (XVII) :
- Composé fluorescent selon l'une quelconque des revendications précédentes, pour une utilisation dans le diagnostic de la fonction rénale, de préférence dans la détermination du débit de filtration glomérulaire (GFR) chez un mammifère.
- Formulation de diagnostic pour une utilisation dans le diagnostic de la fonction rénale, comprenant au moins un composé fluorescent selon l'une quelconque des revendications 1 à 9.
- Procédé de criblage pour l'identification d'un agent de test approprié pour le traitement d'une maladie rénale chronique chez un mammifère comprenant :i) l'administration, à un modèle animal non humain d'une maladie rénale chronique, de l'agent de test et d'au moins un composé fluorescent selon l'une quelconque des revendications 1 à 9, où l'au moins un composé fluorescent est administré après l'agent de test ;ii) la mesure du débit de filtration glomérulaire (GFR) du modèle animal non humain en détectant et en mesurant l'émission de fluorescence de l'au moins un composé fluorescent, où la détection et la mesure de la fluorescence comprend la détection et la mesure de l'émission de fluorescence émergeant de la peau du modèle animal non humain en réponse à une excitation avec une source de lumière rouge ou de lumière proche infrarouge ;iii) la sélection de l'agent de test qui augmente le débit de filtration glomérulaire.
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US10245329B2 (en) * | 2014-09-08 | 2019-04-02 | Canon Kabushiki Kaisha | Composition having dye and conjugate of polyethyleneglycol and additive and contrast agent for photoacoustic imaging having the same |
EP3596477B1 (fr) * | 2017-03-13 | 2023-06-07 | Bayer Aktiengesellschaft | Procédé de création d'un modèle de lésion rénale pour cribler des molécules pour le traitement d'une lésion rénale |
CN107266929B (zh) * | 2017-06-21 | 2019-10-29 | 四川大学 | 一类以菁染料荧光基团为母体骨架结构的近红外荧光染料及其制备方法与应用 |
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US20220096662A1 (en) * | 2019-02-01 | 2022-03-31 | Nanyang Technological University | Molecular renal probes for detecting acute kidney injury |
CN111363007A (zh) * | 2019-06-28 | 2020-07-03 | 南京大学 | 一种高效主动靶向近红外荧光示踪剂的合成方法 |
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US9632094B2 (en) | 2008-08-22 | 2017-04-25 | Norbert Gretz | Transcutaneous organ function measurement |
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